ABT-263 crystalline forms

ABSTRACT

ABT-263 free base and crystalline forms thereof are suitable active pharmaceutical ingredients for pharmaceutical compositions useful in treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 12/882,576, which was filed Sep. 15, 2010 and published as U.S. Pub.No. 2011/0071151. application Ser. No. 12/882,576 claims prioritybenefit of U.S. provisional application Ser. No. 61/244,051 filed onSep. 20, 2009.

Cross-reference is made to the following pending U.S. applicationscontaining subject matter related to the present application: Ser. No.12/770,122 (published as U.S. Pub. No. 2010/0280031) titled “Lipidformulation of apoptosis promoter”; Ser. No. 12/770,174 (published asU.S. Pub. No. 2010/0278905) titled “Stabilized lipid formulation ofapoptosis promoter”; Ser. No. 12/770,205 (published as U.S. Pub. No.2010/0278921) titled “Solid oral formulation of ABT-263”; and Ser. No.12/770,299 (published as U.S. Pub. No. 2010/0297194) titled “Formulationfor oral administration of apoptosis promoter”, all filed on Apr. 29,2010.

The entire disclosures of each of the above applications areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the apoptosis-promoting agent ABT-263,to solid state forms thereof and formulations containing and/or preparedwith such solid state forms, and to methods of use thereof for treatingdiseases characterized by overexpression of anti-apoptotic Bcl-2 familyproteins. More particularly the invention relates to crystalline formsof ABT-263 useful, for example, as active pharmaceutical ingredient(API) in preparing pharmaceutical compositions for administration ofABT-263 to a subject in need thereof.

BACKGROUND OF THE INVENTION

Evasion of apoptosis is a hallmark of cancer (Hanahan & Weinberg (2000)Cell 100:57-70). Cancer cells must overcome a continual bombardment bycellular stresses such as DNA damage, oncogene activation, aberrant cellcycle progression and harsh microenvironments that would cause normalcells to undergo apoptosis. One of the primary means by which cancercells evade apoptosis is by up-regulation of anti-apoptotic proteins ofthe Bcl-2 family.

Compounds that occupy the BH3 binding groove of Bcl-2 proteins have beendescribed, for example by Bruncko et al. (2007) J. Med. Chem.50:641-662. These compounds have includedN-(4-(4-((4′-chloro-(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene-sulfonamide,otherwise known as ABT-737, which has the formula:

ABT-737 binds with high affinity (<1 nM) to proteins of the Bcl-2 family(specifically Bcl-2, Bcl-X_(L) and Bcl-w). It exhibits single-agentactivity against small-cell lung cancer (SCLC) and lymphoidmalignancies, and potentiates pro-apoptotic effects of otherchemotherapeutic agents. ABT-737 and related compounds, and methods tomake such compounds, are disclosed in U.S. Patent ApplicationPublication No. 2007/0072860 (now issued as U.S. Pat. No. 7,973,161) ofBruncko et al.

More recently, a further series of compounds has been identified havinghigh binding affinity to Bcl-2 family proteins. These compounds, andmethods to make them, are disclosed in U.S. Patent ApplicationPublication No. 2007/0027135 (now issued as U.S. Pat. No. 7,390,799) ofBruncko et al. (herein “the '135 publication”), incorporated byreference herein in its entirety, and can be seen from their formula tobe structurally related to ABT-737.

One compound, identified as “Example 1” in the '135 publication, isN-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide,otherwise known as ABT-263. This compound has a molecular weight of974.6 g/mol and has the formula:

Tse et al. (2008) Cancer Res. 68:3421-3428 and supplementary datathereto available at Cancer Research Online(cancerres.aacrjournals.org/) have reported animal pharmacokineticstudies of ABT-263, synthesized as described in the '135 publication.The drug was formulated in solution in 10% dimethyl sulfoxide (DMSO) inpolyethylene glycol (PEG) 400 or in 10% ethanol/30% PEG400/60% Phosal50-PG™.

A particular type of disease for which improved therapies are needed isnon-Hodgkin's lymphoma (NHL). NHL is the sixth most prevalent type ofnew cancer in the U.S. and occurs primarily in patients 60-70 years ofage. NHL is not a single disease but a family of related diseases, whichare classified on the basis of several characteristics includingclinical attributes and histology.

One method of classification places different histological subtypes intotwo major categories based on natural history of the disease, i.e.,whether the disease is indolent or aggressive. In general, indolentsubtypes grow slowly and are generally incurable, whereas aggressivesubtypes grow rapidly and are potentially curable. Follicular lymphomasare the most common indolent subtype, and diffuse large-cell lymphomasconstitute the most common aggressive subtype. The oncoprotein Bcl-2 wasoriginally described in non-Hodgkin's B-cell lymphoma.

Treatment of follicular lymphoma typically consists ofbiologically-based or combination chemotherapy. Combination therapy withrituximab, cyclophosphamide, doxorubicin, vincristine and prednisone(R-CHOP) is routinely used, as is combination therapy with rituximab,cyclophosphamide, vincristine and prednisone (RCVP). Single-agenttherapy with rituximab (targeting CD20, a phosphoprotein uniformlyexpressed on the surface of B-cells) or fludarabine is also used.Addition of rituximab to chemotherapy regimens can provide improvedresponse rate and increased progression-free survival.

Radioimmunotherapy agents, high-dose chemotherapy and stem celltransplants can be used to treat refractory or relapsed non-Hodgkin'slymphoma. Currently, there is not an approved treatment regimen thatproduces a cure, and current guidelines recommend that patients betreated in the context of a clinical trial, even in a first-linesetting.

First-line treatment of patients with aggressive large B-cell lymphomatypically consists of rituximab, cyclophosphamide, doxorubicin,vincristine and prednisone (R-CHOP), or dose-adjusted etoposide,prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab(DA-EPOCH-R).

Most lymphomas respond initially to any one of these therapies, buttumors typically recur and eventually become refractory. As the numberof regimens patients receive increases, the more chemotherapy-resistantthe disease becomes. Average response to first-line therapy isapproximately 75%, 60% to second-line, 50% to third-line, and about35-40% to fourth-line therapy. Response rates approaching 20% with asingle agent in a multiple relapsed setting are considered positive andwarrant further study.

Current chemotherapeutic agents elicit their antitumor response byinducing apoptosis through a variety of mechanisms. However, many tumorsultimately become resistant to these agents. Bcl-2 and Bcl-X_(L) havebeen shown to confer chemotherapy resistance in short-term survivalassays in vitro and, more recently, in vivo. This suggests that ifimproved therapies aimed at suppressing the function of Bcl-2 andBcl-X_(L) can be developed, such chemotherapy-resistance could besuccessfully overcome.

SUMMARY OF THE INVENTION

The compound ABT-263, when prepared according to Example 1 of the '135publication, is recovered as an amorphous, glassy solid that is not wellsuited as active pharmaceutical ingredient (API) for downstreamformulation. More particularly, this amorphous form of ABT-263 isdifficult and therefore expensive to purify and presents process controlproblems. One approach, exemplified in copending U.S. provisionalapplication Ser. No. 61/174,274 filed on Apr. 30, 2009 (incorporated byreference herein without admission that it constitutes prior art to thepresent invention), is to prepare ABT-263 as a crystalline salt. Inanother approach, the present inventors have now been able to prepare aseries of novel crystalline forms of ABT-263 free base suitable for useas API in a wide variety of formulation types, including those where theAPI is present in particulate form together with excipients, for examplein orally deliverable tablets or capsules.

In one embodiment, the invention providesN-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263) free base in solid crystalline form.

In a further embodiment, the invention provides a solvent-free crystalpolymorph of ABT-263 free base characterized herein and designated FormI ABT-263 free base.

In a still further embodiment, the invention provides a solvent-freecrystal polymorph of ABT-263 free base characterized herein anddesignated Form II ABT-263 free base.

In a variety of still further embodiments, the invention providessolvated crystal forms of ABT-263 free base with organic solvents.

In a still further embodiment, the invention provides a pharmaceuticalcomposition comprising crystalline ABT-263 free base (for example Form Ior Form II as provided above) and one or more pharmaceuticallyacceptable excipients.

In a still further embodiment, the invention provides a process forpreparing a pharmaceutical solution composition of ABT-263 comprisingdissolving crystalline ABT-263 free base (for example Form I or Form IIas provided above) in a pharmaceutically acceptable solvent or mixtureof solvents.

In a still further embodiment, the invention provides a method fortreating a disease characterized by apoptotic dysfunction and/oroverexpression of an anti-apoptotic Bcl-2 family protein, comprisingadministering to a subject having the disease a therapeuticallyeffective amount of ABT-263 free base in crystalline form (for exampleForm I or Form II as provided above) or a pharmaceutical compositioncomprising ABT-263 free base in crystalline form (for example Form I orForm II as provided above) and one or more pharmaceutically acceptableexcipients. Examples of such a disease include many neoplastic diseasesincluding cancers. A specific illustrative type of cancer that can betreated according to the present method is non-Hodgkin's lymphoma.Another specific illustrative type of cancer that can be treatedaccording to the present method is chronic lymphocytic leukemia. Yetanother specific illustrative type of cancer that can be treatedaccording to the present method is acute lymphocytic leukemia, forexample in a pediatric patient.

There is still further provided a method for maintaining in bloodstreamof a human cancer patient, for example a patient having non-Hodgkin'slymphoma, a therapeutically effective plasma concentration of ABT-263and/or one or more metabolites thereof, comprising administering to thesubject a pharmaceutical composition comprising ABT-263 free base incrystalline form (for example Form I or Form II as provided above) andone or more pharmaceutically acceptable excipients, in a dosage amountof about 50 to about 1000 mg ABT-263 per day, at an average dosageinterval of about 3 hours to about 7 days.

Additional embodiments of the invention, including more particularaspects of those provided above, will be found in, or will be evidentfrom, the detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a PXRD scan of solvent-free crystal polymorph Form I ABT-263free base.

FIG. 2 is a PXRD scan of solvent-free crystal polymorph Form II ABT-263free base.

DETAILED DESCRIPTION

The term “free base” is used for convenience herein to refer to ABT-263parent compound as distinct from any salt thereof, while recognizingthat the parent compound is, strictly speaking, zwitterionic and thusdoes not always behave as a true base.

The term “solvent-free” herein refers to crystal lattice of a polymorphsuch as Form I or Form II ABT-263 free base, from which solvent has beenremoved by desolvation. Solvent can be present in small amounts insolid-state particles of the compound without being part of or otherwiseaffecting the crystal structure of the polymorph; such presence ofsolvent is still consistent with the polymorph being “solvent-free” asthe term is used herein.

ABT-263 free base can be prepared by a process as described in Example 1of above-cited U.S. Patent Application Publication No. 2007/0027135 (nowissued as U.S. Pat. No. 7,390,799), the entire disclosure of which isincorporated by reference herein. The product of this process is anamorphous, glassy solid. A powder can be prepared from this product, forexample by freeze-drying or precipitation techniques.

Solvates of ABT-263 free base have been prepared as described below. Thestarting product can be any solid-state form of ABT-263 free base,including the amorphous form prepared according to the '135 publication.

A measured amount of ABT-263 free base (as indicated, any solid-stateform can be used) was suspended in each of a number of solvents orsolvent mixtures as indicated in Table 1. The resulting suspensions wereagitated at ambient temperature, while protected from light. After aperiod of time sufficient to permit solvation of ABT-263 free base ineach case, crystals were harvested by filter centrifugation. Theresulting solvates were characterized by powder X-ray diffraction(PXRD).

TABLE 1 Preparation of ABT-263 free base crystalline solvates Weight ofVolume of Solvent compound (mg) solvent (ml) 2-Propanol 106.2 1.01-Propanol 160.1 1.25 Ethyl acetate:Ethanol (1:3, v/v) 108.7 0.5 Methylacetate:Hexanes (1:1, v/v) 76.2 0.5 Chloroform 110.3 0.5 Methanol 107.31.0 1,4-Dioxane:Hexanes (1:2, v/v) 99.5 0.75 Toluene 104.3 1.0 Benzene100.3 0.5 Ethyl acetate ~250 0.25 Isopropyl acetate ~250 0.25 Methylacetate ~250 0.25 Trifluorotoluene ~250 0.25

PXRD data were collected using a G3000 diffractometer (Inel Corp.,Artenay, France) equipped with a curved position-sensitive detector andparallel-beam optics. The diffractometer was operated with a copperanode tube (1.5 kW fine focus) at 40 kV and 30 mA. An incident-beamgermanium monochromator provided monochromatic radiation. Thediffractometer was calibrated using the attenuated direct beam atone-degree intervals. Calibration was checked using a silicon powderline position reference standard (NIST 640c). The instrument wascomputer-controlled using Symphonix software (Inel Corp., Artenay,France) and the data were analyzed using Jade software (version 6.5,Materials Data, Inc., Livermore, Calif.). The sample was loaded onto analuminum sample holder and leveled with a glass slide.

PXRD peaks for individual solvates determined as above are listed inTables 2-14. Peak positions are typically ±0.2 degrees two-theta (°2θ).

TABLE 2 PXRD peak listing: ABT-263 free base 1-propanol solvate PeakPosition (°2θ) 4.88 6.72 8.79 9.62 12.19 12.53 13.46 13.71 14.51 15.3216.10 17.59 18.20 19.30 19.64 20.38 20.91 23.30

TABLE 3 PXRD peak listing: ABT-263 free base 2-propanol solvate PeakPosition (°2θ) 4.88 6.76 8.78 9.64 12.15 12.49 13.41 13.73 15.30 16.1016.35 17.51 18.26 19.34 19.60 20.33 23.35

TABLE 4 PXRD peak listing: ABT-263 free base benzene solvate PeakPosition (°2θ) 4.28 4.60 7.75 8.54 10.88 11.16 12.49 12.97 15.48 18.1018.42 18.75 19.53 20.19 20.59 21.25

TABLE 5 PXRD peak listing: ABT-263 free base chloroform solvate PeakPosition (°2θ) 4.99 9.61 13.39 13.85 15.85 16.05 16.68 17.60 18.51 19.2519.67 20.10 21.37 23.39 23.78 24.48

TABLE 6 PXRD peak listing: ABT-263 free base 1,4-dioxane/hexanes solvatePeak Position (°2θ) 4.85 8.81 9.61 9.94 12.17 12.49 13.39 13.66 15.3016.20 17.60 18.24 19.27 19.55

TABLE 7 PXRD peak listing: ABT-263 free base methyl acetate/hexanessolvate Peak Position (°2θ) 5.66 7.29 9.31 9.70 10.38 11.34 12.56 12.9314.58 14.88 15.83 17.18 17.71 17.99 18.24 18.63 19.46 20.79 21.16 21.46

TABLE 8 PXRD peak listing: ABT-263 free base methanol solvate PeakPosition (°2θ) 5.03 5.25 5.66 8.88 9.66 10.05 12.53 13.67 13.89 15.5218.54 18.93 19.36 19.96 20.33

TABLE 9 PXRD peak listing: ABT-263 free base toluene solvate PeakPosition (°2θ) 4.48 7.61 8.92 10.85 12.35 12.75 13.34 14.73 15.23 16.4718.33 18.89 19.28 19.92 20.29 21.41 22.31 23.66 24.36

TABLE 10 PXRD peak listing: ABT-263 free base ethanol/ethyl acetatesolvate Peak Position (°2θ) 5.03 6.82 8.89 9.68 9.97 12.41 12.65 13.8014.65 15.60 16.26 17.87 18.52 19.43 19.94

TABLE 11 PXRD peak listing: ABT-263 free base ethyl acetate solvate PeakPosition (°2θ) 5.66 7.32 9.31 9.64 11.36 12.56 14.61 14.85 18.03 18.3118.58 19.56 20.70 21.07

TABLE 12 PXRD peak listing: ABT-263 free base isopropyl acetate solvatePeak Position (°2θ) 5.64 7.36 9.50 11.45 12.52 14.72 15.14 16.89 18.0818.45 19.55 20.49 20.89 21.23

TABLE 13 PXRD peak listing: ABT-263 free base methyl acetate solvatePeak Position (°2θ) 5.63 7.24 9.27 9.66 11.27 12.53 14.51 14.77 15.7816.10 16.44 17.64 17.92 18.15 18.52 19.39 20.70

TABLE 14 PXRD peak listing: ABT-263 free base trifluorotoluene solvatePeak Position (°2θ) 4.49 4.99 9.78 12.35 12.73 13.94 15.51 15.80 17.8118.52 19.56 19.99 20.35 21.00 21.60

In addition, single crystals of anisole, pyridine and 2-propanolsolvates were prepared for crystallographic analysis by the followingmethod. Single crystals were individually mounted on MiTeGen polyimidemounts. Intensity data were collected on a Bruker D8 system equippedwith an APEX II CCD camera. Data were collected at 100 K withgraphite-monochromated Mo Ka radiation (λ=0.71073 {acute over (Å)}).Data were collected in four sets using ω-φ scans with ω steps of 0.5°and φ steps of 90°. The data were collected with 20 s frame exposures.Data were processed using APEX2 software. Corrections for Lorentzpolarization effects were applied. Absorption was negligible. Allstructures were solved using direct methods that yielded thenon-hydrogen atoms. All presented hydrogen atoms were located inFourier-difference electron density maps. All non-hydrogen atoms wererefined anisotropically. Hydrogen atoms associated with carbon atomswere refined in geometrically constrained riding positions. Hydrogenatoms associated with oxygen atoms were included in the locatedpositions. Refinement was achieved with the use of SHELXTLcrystallographic software.

To prepare single crystals of an anisole solvate, amorphous ABT-263 freebase was dissolved in 0.5 ml anisole. Single crystals were observed twodays later. Crystallographic data for the anisole solvate are presentedin Table 15, and PXRD peaks calculated from crystal structure are listedin Table 16.

TABLE 15 Crystallographic information for ABT-263 free base anisolesolvate Lattice Type Orthorhombic Space Group P212121 Cell Length a12.112 Å Cell Length b 14.120 Å Cell Length c 38.710 Å Cell Angle α90.0° Cell Angle β 90.0° Cell Angle γ 90.0° Cell Volume 6620.24 Å³ Z 4

TABLE 16 PXRD peak listing: ABT-263 free base anisole solvate(calculated from crystal structure) Peak Position (°2θ) 4.56 7.74 8.609.62 10.64 11.08 11.81 12.53 12.74 14.68 16.08 17.18 17.34 18.71 19.4219.84 20.37 20.74

To prepare single crystals of a pyridine solvate, crystalline ABT-263free base (900 mg) was suspended in a pyridine/hexanes mixture (8 ml,1:4 v/v). The suspension was allowed to settle and the supernatant wasremoved and heated to 50° C. Amorphous ABT-263 free base (100 mg) wasdissolved in the supernatant at 50° C. and the resulting solution wascooled to room temperature. Single crystals were observed one week laterand were found to be a pyridine solvate. Crystallographic data for thepyridine solvate are presented in Table 17, and PXRD peaks calculatedfrom crystal structure are listed in Table 18.

TABLE 17 Crystallographic information for ABT- 263 free base pyridinesolvate Lattice Type Monoclinic Space Group P21 Cell Length a 13.901 ÅCell Length b 11.931 Å Cell Length c 38.935 Å Cell Angle α 90.0° CellAngle β 90.154°  Cell Angle γ 90.0° Cell Volume 6457.46 Å³ Z 4

TABLE 18 PXRD peak listing: ABT-263 free base pyridine solvate(calculated from crystal structure) Peak Position (°2θ) 4.54 6.75 7.758.68 9.76 10.06 11.72 11.91 12.72 14.74 16.32 16.79 17.33 17.55 18.7019.28 19.72

To prepare single crystals of a 2-propanol solvate, approximately 100 mgABT-263 free base was dissolved in approximately 1 g ethyl acetate. Theresulting solution was added to 2.7 g 2-propanol. Crystalline seeds ofABT-263 free base Form I were added. Single crystals were observed twodays later. Crystallographic data for the 2-propanol solvate arepresented in Table 19, and PXRD peaks calculated from crystal structureare listed in Table 20.

TABLE 19 Crystallographic information for ABT- 263 free base 2-propanolsolvate Lattice Type Monoclinic Space Group P21 Cell Length a 13.834 ÅCell Length b 36.105 Å Cell Length c 19.104 Å Cell Angle α 90.0° CellAngle β 110.56°  Cell Angle γ 90.0° Cell Volume 8934.19 Å³ Z 6

TABLE 20 PXRD peak listing: ABT-263 free base 2-propanol solvate(calculated from crystal structure) Peak Position (°2θ) 4.94 6.82 8.849.84 12.30 12.78 13.66 13.92 15.52 16.24 16.58 17.74 18.54 19.52 19.8620.21 23.55

Comparison with Table 3 shows close correspondence between peakpositions calculated from single crystal data and those determined byPXRD. Minor shifts in some peaks may reflect different temperatureconditions in the two methods (100 K for single crystals; roomtemperature for PXRD).

The suspension crystallization technique described above is only one ofseveral known ways to generate the supersaturation necessary to preparesolvated crystals. Other procedures include:

-   -   anti-solvent addition (ABT-263 is dissolved in a first solvent        or mixture of solvents wherein it is soluble at high        concentration, and an anti-solvent that is miscible with the        first solvent or mixture of solvents is added to the resulting        solution);    -   variants of the above anti-solvent addition procedure, for        example where the solution of ABT-263 is added to the        anti-solvent;    -   temperature gradient (ABT-263 is dissolved in a solvent or        mixture of solvents at elevated temperature, and the resulting        solution is cooled to lower temperatures, e.g., sub-ambient        temperatures);    -   solvent evaporation (ABT-263 is dissolved in a solvent or        mixture of solvents, which is then evaporated); and    -   reactive crystallization (ABT-263 in a form of a salt with an        acid is dissolved in a solvent or mixture of solvents, and the        resulting solution is added to a solution of a neutralizing        agent such as sodium hydroxide, sodium carbonate or sodium        bicarbonate, causing the free base to crystallize out;        alternatively an ABT-263 salt with a base can be used, in which        case pH is adjusted with an acidic neutralizing agent to cause        the free base to crystallize out).

Combinations of the above procedures can be used if desired. Specificdetails such as rate of generating supersaturation (for example by rateof addition of anti-solvent or neutralizing agent, rate of cooling orrate of solvent evaporation) can readily be optimized by one of ordinaryskill in the art without undue experimentation.

Desolvation of the ethanol/ethyl acetate solvate, for example byair-drying, provides a solvent-free crystalline form of ABT-263 freebase. This crystalline form is designated Form I. A PXRD scan of Form IABT-263 free base is shown in FIG. 1. PXRD peaks for Form I ABT-263 freebase are listed in Table 21. A PXRD pattern having peaks substantiallyas indicated therein can be used to identify crystalline ABT-263 freebase, more particularly Form I ABT-263 free base. The phrase“substantially as indicated” in the present context means having peaksthat are not shifted more than about 0.2°2θ from the indicated position.

TABLE 21 PXRD peak listing: solvent-free crystal polymorphForm I ABT-263free base Peak Position (°2θ) 6.21 6.72 9.66 10.92 11.34 12.17 14.2816.40 16.95 17.81 18.03 18.47 19.32 20.10 21.87

Desolvation of most solvates, including 1-propanol, 2-propanol,methanol, dioxane/hexanes, methyl acetate/hexanes, ethyl acetate, methylacetate, isopropyl acetate and chloroform solvates, provides asolvent-free crystalline form of ABT-263 free base that is shown by PXRDto be identical to the crystalline form produced by desolvation of theethanol/ethyl acetate solvate.

Desolvation of the pyridine, anisole and trifluorotoluene solvatesprovides a solvent-free crystalline form of ABT-263 free base that isshown by PXRD to be different from the form produced by desolvation ofthe ethanol/ethyl acetate solvate. The crystalline form derived fromdesolvation of the pyridine, anisole or trifluorotoluene solvate isdesignated Form II. A PXRD scan of Form II ABT-263 free base is shown inFIG. 2. PXRD peaks for Form II ABT-263 free base are listed in Table 22.A PXRD pattern having peaks substantially as indicated therein can beused to identify crystalline ABT-263 free base, more particularly FormII ABT-263 free base.

TABLE 22 PXRD peak listing: solvent-free crystal polymorphForm IIABT-263 free base Peak Position (°2θ) 5.79 8.60 9.34 10.79 11.36 11.5912.76 13.23 13.73 14.01 14.72 15.00 16.28 17.07 17.48 18.75 19.34 19.7120.56 21.35

Desolvation of benzene and toluene solvates has been observed ondifferent occasions to provide crystals identified as Form I or Form II.When a higher crystallinity product is achieved, it most closely matchesForm II.

PXRD peaks especially diagnostic for Form I ABT-263 free base, inparticular for distinguishing Form I from Form II, include the peaks at6.21, 6.72, 12.17, 18.03 and 20.10°2θ, in each case ±0.2°2θ. In oneembodiment, Form I ABT-263 free base is characterized at least by a peakat any one or more of these positions. In another embodiment, Form IABT-263 free base is characterized at least by a peak at each of thesepositions. In yet another embodiment, Form I ABT-263 free base ischaracterized by a peak at each of the positions shown in Table 21.

PXRD peaks especially diagnostic for Form II ABT-263 free base, inparticular for distinguishing Form II from Form I, include the peaks at5.79, 8.60, 12.76, 15.00 and 20.56°2θ, in each case ±0.2°2θ. In oneembodiment, Form II ABT-263 free base is characterized at least by apeak at any one or more of these positions. In another embodiment, FormII ABT-263 free base is characterized at least by a peak at each ofthese positions. In yet another embodiment, Form II ABT-263 free base ischaracterized by a peak at each of the positions shown in Table 22.

Any of the crystalline forms of ABT-263 free base, including solvatedforms, can be useful as API for preparation of pharmaceuticalcompositions. However, solvent-free forms such as Form I and Form II aregenerally preferred for this purpose.

Solvated forms are, as indicated above, useful as process intermediatesin preparation of solvent-free forms such as Form I and Form II. It willtherefore be clear from the disclosure herein that an embodiment of thepresent invention provides ABT-263 free base in a crystalline formsolvated with an organic solvent. The term “an organic solvent” will beunderstood herein to embrace single organic solvents and mixtures oforganic solvents. More particularly according to this embodiment thereis provided a crystalline ABT-263 free base solvate selected from thegroup consisting of 1-propanol, 2-propanol, methanol, benzene, toluene,dioxane/hexanes, methyl acetate/hexanes, ethanol/ethyl acetate, ethylacetate, methyl acetate, isopropyl acetate, chloroform, pyridine,anisole and trifluorotoluene solvates.

It will further be clear from the disclosure herein that an embodimentof the present invention provides a process for preparing Form I ABT-263free base, comprising desolvating an ABT-263 free base solvate selectedfrom the group consisting of 1-propanol, 2-propanol, methanol,dioxane/hexanes, methyl acetate/hexanes, ethanol/ethyl acetate, ethylacetate, methyl acetate, isopropyl acetate and chloroform solvates.

It will still further be clear from the disclosure herein that anembodiment of the present invention provides a process for preparingForm II ABT-263 free base, comprising desolvating an ABT-263 free basesolvate selected from the group consisting of pyridine, anisole andtrifluorotoluene solvates. In a related embodiment, a process forpreparing Form II ABT-263 free base comprises desolvating an ABT-263free base solvate selected from the group consisting of benzene andtoluene solvates.

ABT-263 crystalline free base, for example Form I, Form II or acombination thereof, can be used in preparation of pharmaceuticalcompositions suitable for any route of administration, including oral,to a subject in need thereof. Thus in some embodiments of the presentinvention, a pharmaceutical composition is provided, comprising ABT-263crystalline free base and one or more pharmaceutically acceptableexcipients. Such compositions can be prepared by any known process ofpharmacy. In one embodiment, the composition comprises crystalline FormI ABT-263 free base. In another embodiment, the composition comprisescrystalline Form II ABT-263 free base. According to any of theseembodiments, the composition can be deliverable, for example, by theoral route. Other routes of administration include without limitationparenteral, sublingual, buccal, intranasal, pulmonary, topical,transdermal, intradermal, ocular, otic, rectal, vaginal, intragastric,intracranial, intrasynovial and intra-articular routes.

Where it is desired to provide ABT-263 free base in solution form, forexample in a liquid formulation for oral or parenteral administration,the ABT-263 free base will not, of course, be present in such aformulation in crystalline form; indeed, the presence of crystals isgenerally undesired in such a formulation. However, crystalline ABT-263free base of the present invention can nonetheless be important as APIin a process for preparing such a formulation. Thus the inventionfurther provides a process for preparing a pharmaceutical solutioncomposition of ABT-263 comprising dissolving crystalline ABT-263 freebase in a pharmaceutically acceptable solvent or mixture of solvents. Inone embodiment, the process comprises dissolving crystalline Form IABT-263 free base in a solvent or mixture of solvents. In anotherembodiment, the composition comprises dissolving crystalline Form IIABT-263 free base in a solvent or mixture of solvents.

Even where the desired formulation is one containing ABT-263 free basein amorphous form, for example a solid melt formulation, crystallineABT-263 free base can still be useful as API in a process for preparingsuch a formulation. For example, an illustrative process for preparing asolid dispersion of ABT-263 free base comprises

-   -   (a) dissolving an API comprising (i) crystalline ABT-263 free        base, (ii) a pharmaceutically acceptable water-soluble polymeric        carrier and (iii) a pharmaceutically acceptable surfactant in a        suitable solvent; and    -   (b) removing the solvent to provide a solid matrix comprising        the polymeric carrier and the surfactant and having the ABT-263        free base dispersed in an essentially non-crystalline form        therein.

Another illustrative process comprises adding crystalline ABT-263 freebase to at least one pharmaceutically acceptable polymer and at leastone solubilizer; preparing a homogeneous melt from the resultingmixture; and allowing the melt to solidify to obtain a solid dispersionproduct.

As API, a crystalline form of ABT-263 free base such as Form I, Form IIor mixtures thereof has advantages over the amorphous form hithertoavailable. For example, purification of API to the high degree of purityrequired by most regulatory authorities is more efficient and thereforecosts less where the API is in crystalline as opposed to amorphous form.Physical and chemical stability, and therefore shelf-life of the APIsolid, is also typically better for crystalline than amorphous forms.Ease of handling is improved over the amorphous form, which tends to beoily or sticky. Drying is more straightforward and more easilycontrolled in the case of the crystalline material, which has awell-defined drying or desolvation temperature, than in the case of theamorphous material, which has greater affinity for organic solvents andno well-defined drying temperature. Particle size distribution can becontrolled more readily in crystalline material, for example bymanipulation of the crystallization process. Downstream processing usingcrystalline API permits enhanced process control. In preparing a liquidformulation, for example a solution in a lipid carrier, crystallineABT-263 dissolves faster and has less tendency to form a gel duringdissolution. These advantages are illustrative and non-limiting.

Pharmaceutical compositions comprising crystalline ABT-263 free base, orprepared using crystalline ABT-263 free base as API, contain ABT-263 inan amount that can be therapeutically effective when the composition isadministered to a subject in need thereof according to an appropriateregimen. Dosage amounts are expressed herein as free base equivalentamounts unless the context requires otherwise. Typically, a unit dose(the amount administered at a single time), which can be administered atan appropriate frequency, e.g., twice daily to once weekly, is about 10to about 1,000 mg. Where frequency of administration is once daily(q.d.), unit dose and daily dose are the same. Illustratively, the unitdose of ABT-263 in a composition of the invention can be about 25 toabout 1,000 mg, more typically about 50 to about 500 mg, for exampleabout 50, about 100, about 150, about 200, about 250, about 300, about350, about 400, about 450 or about 500 mg. Where the composition isprepared as a discrete dosage form such as a tablet or capsule, a unitdose can be deliverable in a single dosage form or a small plurality ofdosage forms, most typically 1 to about 10 dosage forms.

The higher the unit dose, the more desirable it becomes to selectexcipients that permit a relatively high loading of API (in this caseABT-263 free base) in the formulation. Typically, the concentration ofABT-263 free base in a formulation prepared according to the inventionis at least about 1%, e.g., about 1% to about 25%, by weight, but lowerand higher concentrations can be acceptable or achievable in specificcases. Illustratively, the ABT-263 free base equivalent concentration invarious embodiments is at least about 2%, e.g., about 2% to about 20%,by weight, for example about 5%, about 10% or about 15%, by weight ofthe formulation.

A composition prepared according to the invention comprises, in additionto the API, one or more pharmaceutically acceptable excipients. If thecomposition is to be prepared in solid form for oral administration, forexample as a tablet or capsule, it typically includes at least one ormore solid diluents and one or more solid disintegrants. Optionally, theexcipients further include one or more binding agents, wetting agentsand/or antifrictional agents (lubricants, anti-adherents and/orglidants). Many excipients have two or more functions in apharmaceutical composition. Characterization herein of a particularexcipient as having a certain function, e.g., diluent, disintegrant,binding agent, etc., should not be read as limiting to that function.Further information on excipients can be found in standard referenceworks such as Handbook of Pharmaceutical Excipients, 3rd ed. (Kibbe, ed.(2000), Washington: American Pharmaceutical Association).

Suitable diluents illustratively include, either individually or incombination, lactose, including anhydrous lactose and lactosemonohydrate; lactitol; maltitol; mannitol; sorbitol; xylitol; dextroseand dextrose monohydrate; fructose; sucrose and sucrose-based diluentssuch as compressible sugar, confectioner's sugar and sugar spheres;maltose; inositol; hydrolyzed cereal solids; starches (e.g., cornstarch, wheat starch, rice starch, potato starch, tapioca starch, etc.),starch components such as amylose and dextrates, and modified orprocessed starches such as pregelatinized starch; dextrins; cellulosesincluding powdered cellulose, microcrystalline cellulose, silicifiedmicrocrystalline cellulose, food grade sources of α- and amorphouscellulose and powdered cellulose, and cellulose acetate; calcium saltsincluding calcium carbonate, tribasic calcium phosphate, dibasic calciumphosphate dihydrate, monobasic calcium sulfate monohydrate, calciumsulfate and granular calcium lactate trihydrate; magnesium carbonate;magnesium oxide; bentonite; kaolin; sodium chloride; and the like. Suchdiluents, if present, typically constitute in total about 5% to about95%, for example about 20% to about 90%, or about 50% to about 85%, byweight of the composition. The diluent or diluents selected preferablyexhibit suitable flow properties and, where tablets are desired,compressibility.

Microcrystalline cellulose and silicified microcrystalline cellulose areparticularly useful diluents, and are optionally used in combinationwith a water-soluble diluent such as mannitol. Illustratively, asuitable weight ratio of microcrystalline cellulose or silicifiedmicrocrystalline cellulose to mannitol is about 10:1 to about 1:1, butratios outside this range can be useful in particular circumstances.

Suitable disintegrants include, either individually or in combination,starches including pregelatinized starch and sodium starch glycolate;clays; magnesium aluminum silicate; cellulose-based disintegrants suchas powdered cellulose, microcrystalline cellulose, methylcellulose,low-substituted hydroxypropylcellulose, carmellose, carmellose calcium,carmellose sodium and croscarmellose sodium; alginates; povidone;crospovidone; polacrilin potassium; gums such as agar, guar, locustbean, karaya, pectin and tragacanth gums; colloidal silicon dioxide; andthe like. One or more disintegrants, if present, typically constitute intotal about 0.2% to about 30%, for example about 0.5% to about 20%, orabout 1% to about 10%, by weight of the composition.

Sodium starch glycolate is a particularly useful disintegrant, andtypically constitutes in total about 1% to about 20%, for example about2% to about 15%, or about 5% to about 10%, by weight of the composition.

Binding agents or adhesives are useful excipients, particularly wherethe composition is in the form of a tablet. Such binding agents andadhesives should impart sufficient cohesion to the blend being tabletedto allow for normal processing operations such as sizing, lubrication,compression and packaging, but still allow the tablet to disintegrateand the composition to be absorbed upon ingestion. Suitable bindingagents and adhesives include, either individually or in combination,acacia; tragacanth; glucose; polydextrose; starch includingpregelatinized starch; gelatin; modified celluloses includingmethylcellulose, carmellose sodium, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose, hydroxyethylcellulose and ethylcellulose;dextrins including maltodextrin; zein; alginic acid and salts of alginicacid, for example sodium alginate; magnesium aluminum silicate;bentonite; polyethylene glycol (PEG); polyethylene oxide; guar gum;polysaccharide acids; polyvinylpyrrolidone (povidone or PVP), forexample povidone K-15, K-30 and K-29/32; polyacrylic acids (carbomers);polymethacrylates; and the like. One or more binding agents and/oradhesives, if present, typically constitute in total about 0.5% to about25%, for example about 1% to about 15%, or about 1.5% to about 10%, byweight of the composition.

Povidone and hydroxypropylcellulose, either individually or incombination, are particularly useful binding agents for tabletformulations, and, if present, typically constitute about 0.5% to about15%, for example about 1% to about 10%, or about 2% to about 8%, byweight of the composition.

Wetting agents, if present, are normally selected to maintain the drugin close association with water, a condition that can improvebioavailability of the composition. Non-limiting examples of surfactantsthat can be used as wetting agents include, either individually or incombination, quaternary ammonium compounds, for example benzalkoniumchloride, benzethonium chloride and cetylpyridinium chloride; dioctylsodium sulfosuccinate; polyoxyethylene alkylphenyl ethers, for examplenonoxynol 9, nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethyleneand polyoxypropylene block copolymers); polyoxyethylene fatty acidglycerides and oils, for example polyoxyethylene (8) caprylic/capricmono- and diglycerides, polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example ceteth-10, laureth-4, laureth-23, oleth-2, oleth-10,oleth-20, steareth-2, steareth-10, steareth-20, steareth-100 andpolyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acidesters, for example polyoxyethylene (20) stearate, polyoxyethylene (40)stearate and polyoxyethylene (100) stearate; sorbitan esters, forexample sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate; polyoxyethylene sorbitanesters, for example polysorbate 20 and polysorbate 80; propylene glycolfatty acid esters, for example propylene glycol laurate; sodium laurylsulfate; fatty acids and salts thereof, for example oleic acid, sodiumoleate and triethanolamine oleate; glyceryl fatty acid esters, forexample glyceryl monooleate, glyceryl monostearate and glycerylpalmitostearate; tyloxapol; and the like. One or more wetting agents, ifpresent, typically constitute in total about 0.1% to about 15%, forexample about 0.2% to about 10%, or about 0.5% to about 7%, by weight ofthe composition.

Nonionic surfactants, more particularly poloxamers, are examples ofwetting agents that can be useful herein. Illustratively, a poloxamersuch as Pluronic™ F127, if present, can constitute about 0.1% to about10%, for example about 0.2% to about 7%, or about 0.5% to about 5%, byweight of the composition.

Lubricants reduce friction between a tableting mixture and tabletingequipment during compression of tablet formulations. Suitable lubricantsinclude, either individually or in combination, glyceryl behenate;stearic acid and salts thereof, including magnesium, calcium and sodiumstearates; hydrogenated vegetable oils; glyceryl palmitostearate; talc;waxes; sodium benzoate; sodium acetate; sodium fumarate; sodium stearylfumarate; PEGs (e.g., PEG 4000 and PEG 6000); poloxamers; polyvinylalcohol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate;and the like. One or more lubricants, if present, typically constitutein total about 0.05% to about 10%, for example about 0.1% to about 5%,or about 0.2% to about 2%, by weight of the composition. Sodium stearylfumarate is a particularly useful lubricant.

Anti-adherents reduce sticking of a tablet formulation to equipmentsurfaces. Suitable anti-adherents include, either individually or incombination, talc, colloidal silicon dioxide, starch, DL-leucine, sodiumlauryl sulfate and metallic stearates. One or more anti-adherents, ifpresent, typically constitute in total about 0.05% to about 10%, forexample about 0.1% to about 7%, or about 0.2% to about 5%, by weight ofthe composition. Colloidal silicon dioxide is a particularly usefulanti-adherent.

Glidants improve flow properties and reduce static in a tabletingmixture. Suitable glidants include, either individually or incombination, colloidal silicon dioxide, starch, powdered cellulose,sodium lauryl sulfate, magnesium trisilicate and metallic stearates. Oneor more glidants, if present, typically constitute in total about 0.05%to about 10%, for example about 0.1% to about 7%, or about 0.2% to about5%, by weight of the composition. Colloidal silicon dioxide is aparticularly useful glidant.

Other excipients such as buffering agents, stabilizers, antioxidants,antimicrobials, colorants, flavors and sweeteners are known in thepharmaceutical art and can be used in compositions of the presentinvention. Tablets can be uncoated or can comprise a core that iscoated, for example with a nonfunctional film or a release-modifying orenteric coating. Capsules can have hard or soft shells comprising, forexample, gelatin (in the form of hard gelatin capsules or soft elasticgelatin capsules), starch, carrageenan and/or HPMC, optionally togetherwith one or more plasticizers.

A solid orally deliverable composition of the present invention is notlimited by any process used to prepare it. Any suitable process ofpharmacy can be used, including dry blending with or without directcompression, and wet or dry granulation.

If the composition is to be prepared in liquid (including encapsulatedliquid) form, the API (crystalline ABT-263 free base) can be, forexample, dissolved in a suitable carrier, typically one comprising alipid solvent for the API. The higher the unit dose, the more desirableit becomes to select a carrier that permits a relatively highconcentration of the drug in solution therein. Typically, the free baseequivalent concentration of API in the carrier is at least about 10mg/ml, e.g., about 10 to about 500 mg/ml, but lower and higherconcentrations can be acceptable or achievable in specific cases.Illustratively, the drug concentration in various embodiments is atleast about 10 mg/ml, e.g., about 10 to about 250 mg/ml, or at leastabout 20 mg/ml, e.g., about 20 to about 200 mg/ml, for example about 20,about 25, about 30, about 40, about 50, about 75, about 100 or about 150mg/ml.

The carrier can be substantially non-aqueous, i.e., having no water, orhaving an amount of water that is small enough to be, in practicalterms, essentially non-deleterious to performance or properties of thecomposition. Typically, the carrier comprises zero to less than about 5%by weight water. It will be understood that certain ingredients usefulherein can bind small amounts of water on or within their molecules orsupramolecular structures; such bound water if present does not affectthe “substantially non-aqueous” character of a carrier as definedherein.

In some embodiments, the carrier comprises one or more glyceridematerials. Suitable glyceride materials include, without limitation,medium to long chain mono-, di- and triglycerides. The term “mediumchain” herein refers to hydrocarbyl chains individually having no lessthan about 6 and less than about 12 carbon atoms, including for exampleC₈ to C₁₀ chains. Thus glyceride materials comprising caprylyl andcapryl chains, e.g., caprylic/capric mono-, di- and/or triglycerides,are examples of “medium chain” glyceride materials herein. The term“long chain” herein refers to hydrocarbyl chains individually having atleast about 12, for example about 12 to about 18, carbon atoms,including for example lauryl, myristyl, cetyl, stearyl, oleyl, linoleyland linolenyl chains. Medium to long chain hydrocarbyl groups in theglyceride materials can be saturated, mono- or polyunsaturated.

In one embodiment the carrier comprises a medium chain and/or a longchain triglyceride material. A suitable example of a medium chaintriglyceride material is a caprylic/capric triglyceride product such as,for example, Captex 355 EP™ of Abitec Corp. and products substantiallyequivalent thereto. Suitable examples of long chain triglyceridesinclude any pharmaceutically acceptable vegetable oil, for examplecanola, coconut, corn, cottonseed, flaxseed, olive, palm, peanut,safflower, sesame, soy and sunflower oils, and mixtures of such oils.Oils of animal, particularly marine animal, origin can also be used,including for example fish oil.

A carrier system that has been found particularly useful comprises twoessential components: a phospholipid, and a pharmaceutically acceptablesolubilizing agent for the phospholipid. It will be understood thatreference in the singular to a (or the) phospholipid, solubilizing agentor other formulation ingredient herein includes the plural; thuscombinations, for example mixtures, of more than one phospholipid, ormore than one solubilizing agent, are expressly contemplated herein. Thesolubilizing agent, or the combination of solubilizing agent andphospholipid, also solubilizes the drug, although other carrieringredients, such as a surfactant or an alcohol such as ethanol,optionally present in the carrier can in some circumstances provideenhanced solubilization of the drug.

Any pharmaceutically acceptable phospholipid or mixture of phospholipidscan be used. In general such phospholipids are phosphoric acid estersthat yield on hydrolysis phosphoric acid, fatty acid(s), an alcohol anda nitrogenous base. Pharmaceutically acceptable phospholipids caninclude without limitation phosphatidylcholines, phosphatidylserines andphosphatidylethanolamines. In one embodiment the composition comprisesphosphatidylcholine, derived for example from natural lecithin. Anysource of lecithin can be used, including animal sources such as eggyolk, but plant sources are generally preferred. Soy is a particularlyrich source of lecithin that can provide phosphatidylcholine for use inthe present invention.

Illustratively, a suitable amount of phospholipid is about 15% to about75%, for example about 30% to about 60%, by weight of the carrier,although greater and lesser amounts can be useful in particularsituations.

Ingredients useful as components of the solubilizing agent are notparticularly limited and will depend to some extent on the desiredconcentration of drug and of phospholipid. In one embodiment, thesolubilizing agent comprises one or more glycols, one or more glycolidesand/or one or more glyceride materials.

Glycols are generally suitable only for non-encapsulated formulations orwhere a soft capsule shell is to be used, and tend to be incompatiblewith hard shells such as hard gelatin shells. Suitable glycols includepropylene glycol and polyethylene glycols (PEGs) having molecular weightof about 200 to about 1,000 g/mol, e.g., PEG-400, which has an averagemolecular weight of about 400 g/mol. Such glycols can provide relativelyhigh solubility of the drug; however the potential for oxidativedegradation of ABT-263 can be increased when in solution in a carriercomprising such glycols, for example because of the tendency of glycolsto produce superoxides, peroxides and/or free hydroxyl radicals. Thehigher the glycol content of the carrier, the greater may be thetendency for degradation of the ABT-263. In one embodiment, therefore,one or more glycols are present in a total glycol amount of at leastabout 1% but less than about 50%, for example less than about 30%, lessthan about 20%, less than about 15% or less than about 10% by weight ofthe carrier. In another embodiment, the carrier comprises substantiallyno glycol.

Glycolides are glycols such as propylene glycol or PEG esterified withone or more organic acids, for example medium- to long-chain fattyacids. Suitable examples include propylene glycol monocaprylate,propylene glycol monolaurate and propylene glycol dilaurate productssuch as, for example. Capmul PG-8™, Capmul PG-12™ and Capmul PG-2L™respectively of Abitec Corp. and products substantially equivalentthereto.

Suitable glyceride materials for use together with a phospholipidinclude, without limitation, those mentioned above. Where one or moreglyceride materials are present as a major component of the solubilizingagent, a suitable total amount of glycerides is an amount effective tosolubilize the phospholipid and, in combination with other components ofthe carrier, effective to maintain the drug and antioxidant in solution.For example, glyceride materials such as medium chain and/or long chaintriglycerides can be present in a total glyceride amount of about 5% toabout 70%, for example about 15% to about 60% or about 25% to about 50%,by weight of the carrier.

Additional solubilizing agents that are other than glycols, glycolidesor glyceride materials can be included if desired. Such agents, forexample N-substituted amide solvents such as dimethylformamide (DMF) andN,N-dimethylacetamide (DMA), can, in specific cases, assist in raisingthe limit of solubility of the drug in the carrier, thereby permittingincreased drug loading. However, the carriers useful herein generallyprovide adequate solubility of ABT-263 without such additional agents.

Even when a sufficient amount of a glycol, glycolide or glyceridematerial is present to solubilize the phospholipid, the resultingcarrier solution and/or the drug-carrier system may be rather viscousand difficult or inconvenient to handle. In such cases it may be founddesirable to include in the carrier a viscosity reducing agent in anamount effective to provide acceptably low viscosity. An example of suchan agent is an alcohol, more particularly ethanol, which is preferablyintroduced in a form that is substantially free of water, for example99% ethanol, dehydrated alcohol USP or absolute ethanol. Excessivelyhigh concentrations of ethanol should, however, generally be avoided.This is particularly true where, for example, the drug-carrier system isto be administered in a gelatin capsule, because of the tendency of highethanol concentrations to result in mechanical failure of the capsule.In general, suitable amounts of ethanol are 0% to about 25%, for exampleabout 1% to about 20% or about 3% to about 15%, by weight of thecarrier. Glycols such as propylene glycol or PEG and medium-chain mono-and diglycerides (for example caprylic/capric mono- and diglycerides)can also be helpful to lower viscosity; where the drug-carrier system isto be encapsulated in a hard capsule such as a hard gelatin capsule,medium-chain mono- and diglycerides are particularly useful in thisregard.

Optionally, the carrier further comprises a pharmaceutically acceptablenon-phospholipid surfactant. One of skill in the art will be able toselect a suitable surfactant for use in a composition of the invention.Illustratively, a surfactant such as polysorbate 80 can be included inan amount of 0% to about 5%, for example 0% to about 2% or 0% to about1%, by weight of the carrier.

Conveniently, pre-blended products are available containing a suitablephospholipid+solubilizing agent combination for use in compositions ofthe present invention. Pre-blended phospholipid+solubilizing agentproducts can be advantageous in improving ease of preparation of thepresent compositions.

An illustrative example of a pre-blended phospholipid+solubilizing agentproduct is Phosal 50 PG™, available from Phospholipid GmbH, Germany,which comprises, by weight, not less than 50% phosphatidylcholine, notmore than 6% lysophosphatidylcholine, about 35% propylene glycol, about3% mono- and diglycerides from sunflower oil, about 2% soy fatty acids,about 2% ethanol, and about 0.2% ascorbyl palmitate.

Another illustrative example is Phosal 53 MCT™, also available fromPhospholipid GmbH, which contains, by weight, not less than 53%phosphatidylcholine, not more than 6% lysophosphatidylcholine, about 29%medium chain triglycerides, 3-6% (typically about 5%) ethanol, about 3%mono- and diglycerides from sunflower oil, about 2% oleic acid, andabout 0.2% ascorbyl palmitate (reference composition). A product havingthe above or substantially equivalent composition, whether sold underthe Phosal 53 MCT™ brand or otherwise, is generically referred to hereinas “phosphatidylcholine+medium chain triglycerides 53/29”. A producthaving “substantially equivalent composition” in the present contextmeans having a composition sufficiently similar to the referencecomposition in its ingredient list and relative amounts of ingredientsto exhibit no practical difference in properties with respect toutilization of the product herein.

Yet another illustrative example is Lipoid S75™, available from LipoidGmbH, which contains, by weight, not less than 70% phosphatidylcholinein a solubilizing system. This can be further blended with medium-chaintriglycerides, for example in a 30/70 weight/weight mixture, to providea product (“Lipoid S75™ MCT”) containing, by weight, not less than 20%phosphatidylcholine, 2-4% phosphatidylethanolamine, not more than 1.5%lysophosphatidylcholine, and 67-73% medium-chain triglycerides.

Yet another illustrative example is Phosal 50 SA+™, available fromPhospholipid GmbH, which contains, by weight, not less than 50%phosphatidylcholine and not more than 6% lysophosphatidylcholine in asolubilizing system comprising safflower oil and other ingredients.

The phosphatidylcholine component of each of these pre-blended productsis derived from soy lecithin. Products of substantially equivalentcomposition may be obtainable from other suppliers.

A pre-blended product such as Phosal 50 PG™, Phosal 53 MCT™, Lipoid S75™MCT or Phosal 50 SA+™ can, in some embodiments, constitute substantiallythe entire carrier system. In other embodiments, additional ingredientsare present, for example ethanol (additional to any that may be presentin the pre-blended product), non-phospholipid surfactant such aspolysorbate 80, polyethylene glycol and/or other ingredients. Suchadditional ingredients, if present, are typically included in only minoramounts. Illustratively, phosphatidylcholine+medium chain triglycerides53/29 can be included in the carrier in an amount of about 50% to 100%,for example about 80% to 100%, by weight of the carrier.

U.S. Patent Application Publication No. 2009/0149461 of Krivoshik,incorporated by reference herein without admission that it constitutesprior art to the present invention, describes a clinical trial using asstudy drug ABT-263 in a form of a powder for oral solution when mixed(25 mg/ml) in diluents listed as Phosal 53 MCT™ and dehydrated alcohol.

ABT-263 is susceptible to degradation in an oxidative environment; thusit will often be found desirable to include an antioxidant in thecomposition. Antioxidants used in pharmaceutical compositions are mosttypically agents that inhibit generation of oxidative species such astriplet or singlet oxygen, superoxides, peroxide and free hydroxylradicals, or agents that scavenge such oxidative species as they aregenerated. Examples of commonly used antioxidants of these classesinclude butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),retinyl palmitate, tocopherol, propyl gallate, ascorbic acid andascorbyl palmitate. Such antioxidants can be used; alternativelyheavier-chalcogen antioxidants may be particularly useful.

A chalcogen is an element of Group 16 (formerly known as Group VIA) ofthe periodic table, including oxygen, sulfur, selenium and tellurium. A“heavier-chalcogen” herein means a chalcogen having heavier atomicweight than oxygen, specifically including sulfur and selenium. A“heavier-chalcogen antioxidant” or “HCA” is a compound havingantioxidant properties that contains one or more oxidizable sulfur orselenium, most particularly sulfur, atoms. HCAs are believed, withoutbeing bound by theory, to function primarily as competitive substrates,i.e., as “sacrificial” antioxidants, which are preferentially attackedby oxidative species thereby protecting the drug from excessivedegradation.

In some embodiments, the HCA comprises one or more antioxidant compoundsof Formula II:

where

n is 0, 1 or 2;

Y¹ is S or Se;

Y² is NHR¹, OH or H, where R¹ is alkyl or alkylcarbonyl;

Y³ is COOR² or CH₂OH, where R² is H or alkyl; and

R³ is H or alkyl;

where alkyl groups are independently optionally substituted with one ofmore substituents independently selected from the group consisting ofcarboxyl, alkylcarbonyl, alkoxycarbonyl, amino and alkylcarbonylamino; apharmaceutically acceptable salt thereof; or, where Y¹ is S and R³ is H,an —S—S— dimer thereof or pharmaceutically acceptable salt of suchdimer.

In other embodiments, the HCA is an antioxidant compound of Formula III:

where

-   -   Y is S, Se or S—S; and    -   R⁴ and R⁵ are independently selected from H, alkyl and        (CH₂)_(n)R⁶ where n is 0-10 and R⁶ is arylcarbonyl,        alkylcarbonyl, alkoxycarbonyl, carboxyl or CHR⁷R⁸-substituted        alkyl, where R⁷ and R⁸ are independently CO₂R⁹, CH₂OH, hydrogen        or NHR¹⁰, where R⁹ is H, alkyl, substituted alkyl or arylalkyl        and R¹⁰ is hydrogen, alkyl, alkylcarbonyl or alkoxycarbonyl.

An “alkyl” substituent or an “alkyl” or “alkoxy” group forming part of asubstituent according to Formula II or Formula III is one having 1 toabout 18 carbon atoms and can consist of a straight or branched chain.

An “aryl” group forming part of a substituent according to Formula IIIis a phenyl group, unsubstituted or substituted with one or morehydroxy, alkoxy or alkyl groups.

In some embodiments, R¹ in Formula II is C₁₋₄ alkyl (e.g., methyl orethyl) or (C₁₋₄ alkyl)carbonyl (e.g., acetyl).

In some embodiments, R² in Formula II is H or C₁₋₁₈ alkyl, for examplemethyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g.,n-butyl, isobutyl or t-butyl), octyl (e.g., n-octyl or 2-ethylhexyl),dodecyl (e.g., lauryl), tridecyl, tetradecyl, hexadecyl or octadecyl(e.g., stearyl).

R³ is typically H or C₁₋₄ alkyl (e.g., methyl or ethyl).

The HCA can be, for example, a natural or synthetic amino acid or aderivative thereof such as an alkyl ester or N-acyl derivative, or asalt of such amino acid or derivative. Where the amino acid orderivative thereof is derived from a natural source it is typically inthe L-configuration; however it is understood that D-isomers andD,L-isomer mixtures can be substituted if necessary.

Non-limiting examples of HCAs useful herein includeβ-alkylmercaptoketones, cysteine, cystine, homocysteine, methionine,thiodiglycolic acid, thiodipropionic acid, thioglycerol, selenocysteine,selenomethionine and salts, esters, amides and thioethers thereof; andcombinations thereof. More particularly, one or more HCAs can beselected from N-acetylcysteine, N-acetylcysteine butyl ester,N-acetylcysteine dodecyl ester, N-acetyl-cysteine ethyl ester,N-acetylcysteine methyl ester, N-acetylcysteine octyl ester,N-acetyl-cysteine propyl ester, N-acetylcysteine stearyl ester,N-acetylcysteine tetradecyl ester, N-acetylcysteine tridecyl ester,N-acetylmethionine, N-acetylmethionine butyl ester, N-acetylmethioninedodecyl ester, N-acetylmethionine ethyl ester, N-acetylmethionine methylester, N-acetylmethionine octyl ester, N-acetylmethionine propyl ester,N-acetylmethionine stearyl ester, N-acetylmethionine tetradecyl ester,N-acetylmethionine tridecyl ester, N-acetyl-selenocysteine,N-acetylselenocysteine butyl ester, N-acetylselenocysteine dodecylester, N-acetylselenocysteine ethyl ester, N-acetylselenocysteine methylester, N-acetylseleno-cysteine octyl ester, N-acetylselenocysteinepropyl ester, N-acetylselenocysteine stearyl ester,N-acetylselenocysteine tetradecyl ester, N-acetylselenocysteine tridecylester, N-acetylseleno-methionine, N-acetylselenomethionine butyl ester,N-acetylselenomethionine dodecyl ester, N-acetylselenomethionine ethylester, N-acetylselenomethionine methyl ester, N-acetyl-selenomethionineoctyl ester, N-acetylselenomethionine propyl ester,N-acetylseleno-methionine stearyl ester, N-acetylselenomethioninetetradecyl ester, N-acetylseleno-methionine tridecyl ester, cysteine,cysteine butyl ester, cysteine dodecyl ester, cysteine ethyl ester,cysteine methyl ester, cysteine octyl ester, cysteine propyl ester,cysteine stearyl ester, cysteine tetradecyl ester, cysteine tridecylester, cystine, cystine dibutyl ester, cystine di(dodecyl) ester,cystine diethyl ester, cystine dimethyl ester, cystine dioctyl ester,cystine dipropyl ester, cystine distearyl ester, cystine di(tetradecyl)ester, cystine di(tridecyl) ester, N,N-diacetylcystine,N,N-diacetylcystine dibutyl ester, N,N-diacetylcystine diethyl ester,N,N-diacetylcystine di(dodecyl) ester, N,N-diacetylcystine dimethylester, N,N-diacetylcystine dioctyl ester, N,N-diacetylcystine dipropylester, N,N-diacetylcystine distearyl ester, N,N-diacetylcystinedi(tetradecyl) ester, N,N-diacetylcystine di(tridecyl) ester, dibutylthiodiglycolate, dibutyl thiodipropionate, di(dodecyl) thiodiglycolate,di(dodecyl) thiodipropionate, diethyl thiodiglycolate, diethylthiodipropionate, dimethyl thiodiglycolate, dimethyl thiodipropionate,dioctyl thiodiglycolate, dioctyl thiodipropionate, dipropylthiodiglycolate, dipropyl thiodipropionate, distearyl thiodiglycolate,distearyl thiodipropionate, di(tetradecyl) thiodiglycolate,di(tetradecyl) thiodipropionate, homocysteine, homocysteine butyl ester,homocysteine dodecyl ester, homocysteine ethyl ester, homocysteinemethyl ester, homocysteine octyl ester, homocysteine propyl ester,homocysteine stearyl ester, homocysteine tetradecyl ester, homocysteinetridecyl ester, methionine, methionine butyl ester, methionine dodecylester, methionine ethyl ester, methionine methyl ester, methionine octylester, methionine propyl ester, methionine stearyl ester, methioninetetradecyl ester, methionine tridecyl ester, S-methylcysteine,S-methyl-cysteine butyl ester, S-methylcysteine dodecyl ester,S-methylcysteine ethyl ester, S-methyl-cysteine methyl ester,S-methylcysteine octyl ester, S-methylcysteine propyl ester,S-methyl-cysteine stearyl ester, S-methylcysteine tetradecyl ester,S-methylcysteine tridecyl ester, selenocysteine, selenocysteine butylester, selenocysteine dodecyl ester, selenocysteine ethyl ester,selenocysteine methyl ester, selenocysteine octyl ester, selenocysteinepropyl ester, selenocysteine stearyl ester, selenocysteine tetradecylester, selenocysteine tridecyl ester, selenomethionine, selenomethioninebutyl ester, selenomethionine dodecyl ester, seleno-methionine ethylester, selenomethionine methyl ester, selenomethionine octyl ester,seleno-methionine propyl ester, selenomethionine stearyl ester,selenomethionine tetradecyl ester, selenomethionine tridecyl ester,thiodiglycolic acid, thiodipropionic acid, thioglycerol, isomers andmixtures of isomers thereof, and salts thereof.

Salts of HCA compounds can be acid addition salts such as the acetate,adipate, alginate, bicarbonate, citrate, aspartate, benzoate,benzenesulfonate (besylate), bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, formate, fumarate, glycerophosphate,glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, lactobionate, lactate, maleate,mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate,oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate,succinate, tartrate, thiocyanate, trichloroacetate, trifluoroacetate,para-toluenesulfonate and undecanoate salts. In a particular embodiment,the hydrochloride salt of one of the compounds individually mentionedabove is present in the composition in an antioxidant effective amount.

Without being bound by theory, it is generally believed thatheavier-chalcogen antioxidants such as those exemplified above protectABT-263 by being themselves more readily oxidizable and, therefore,being oxidized preferentially over the ABT-263. In general, for thismode of operation to provide an acceptable degree of protection forABT-263, an antioxidant of Formula II or Formula III must be present ina substantial amount, for example in a molar ratio to ABT-263 of atleast about 1:10. In some embodiments, the molar ratio of antioxidant toABT-263 is about 1:10 to about 2:1, for example about 1:5 to about1.5:1. Best results will sometimes be obtained when the molar ratio isapproximately 1:1, i.e., about 8:10 to about 10:8.

Notwithstanding the antioxidant efficacy of sulfur-containingantioxidants of Formula II or Formula III, it has been found that, atmolar ratios of approximately 1:1, such antioxidants have a tendency toresult in solutions that become cloudy upon storage, when ABT-263 isused in the form of its free base.

However, ABT-263 free base has been found to be less susceptible tosulfoxide formation than ABT-263 in salt form, for example ABT-263bis-HCl, when formulated in lipid solution (but in the absence ofantioxidant). To take advantage of this finding, a different class ofsulfur-containing antioxidants can be used with ABT-263 free base,namely inorganic antioxidants of the sulfite, bisulfite, metabisulfiteand thiosulfate classes. To complicate matters, these antioxidants arepoorly lipid-soluble and, where a liquid formulation is desired, must beintroduced to the carrier or drug-carrier system in aqueous solution.Presence of water promotes sulfoxide formation in ABT-263 solutions, thevery effect that is sought to be minimized. To restrict the amount ofadded water, poorly lipid-soluble antioxidants are, in one embodiment ofthe present invention, added at much lower concentrations than thoseproviding molar equivalence to the concentration of ABT-263.

Where a poorly lipid-soluble antioxidant such as a sulfite, bisulfite,metabisulfite or thiosulfate antioxidant is used, it is accompanied inthe drug-carrier system by water in an amount not exceeding about 1% byweight, for example about 0.2% to about 0.8% by weight. The amount ofsuch antioxidant that can be introduced in such a small amount of watertypically does not exceed about 0.2% by weight, and is for example anamount of about 0.02% to about 0.2%, or about 0.05% to about 0.15%, byweight, of the drug-carrier system.

To minimize the amount of water added to the formulation, it isdesirable to provide the antioxidant in the form of a relativelyconcentrated aqueous stock solution, for example having at least about10% by weight antioxidant. However, it has been found that where anexcessively concentrated stock solution (e.g., about 20% or higher) isused, this can result in undesirable precipitation of solids in theformulation. Suitable concentrations of antioxidant in the stocksolution are typically about 10% to about 18%, illustratively about 15%,by weight.

Sodium and potassium salts of sulfites, bisulfites, metabisulfites andthiosulfates are useful antioxidants according to the presentembodiment; more particularly sodium and potassium metabisulfites.

To further minimize sulfoxide formation, a chelating agent such as EDTAor a salt thereof (e.g., disodium EDTA or calcium disodium EDTA) isoptionally added, for example in an amount of about 0.002% to about0.02% by weight of the drug-carrier system. EDTA can be added as anaqueous stock solution in the same manner as the antioxidant. Theantioxidant and EDTA can, if desired, be added as components of the samestock solution. Chelating agents sequester metal ions that can promoteoxidative degradation.

Even at the very low antioxidant concentrations contemplated herein(typically the molar ratio of poorly lipid-soluble antioxidant toABT-263 according to the present embodiment is no greater than about1:20), sulfoxide formation has been found to remain within acceptablelimits.

Sulfoxide formation can be further minimized by selecting formulationingredients having low peroxide value. Peroxide value is a wellestablished property of pharmaceutical excipients and is generallyexpressed (as herein) in units corresponding to milliequivalents ofperoxides per kilogram of excipient (meq/kg). Some excipients inherentlyhave low peroxide value, but others, for example those havingunsaturated fatty acid such as oleyl moieties and/or polyoxyethylenechains, can be sources of peroxides. In the case of polysorbate 80, forexample, it is preferable to select a source of polysorbate 80 having aperoxide value not greater than about 5, for example not greater thanabout 2. Suitable sources include Crillet 4HP™ and Super-Refined Tween80™, both available from Croda.

Without being bound by theory, it is believed that the therapeuticefficacy of ABT-263 is due at least in part to its ability to bind to aBcl-2 family protein such as Bcl-2, Bcl-X_(L) or Bcl-w in a way thatinhibits the anti-apoptotic action of the protein, for example byoccupying the BH3 binding groove of the protein.

In still further embodiments of the invention, there is provided amethod for treating a disease characterized by apoptotic dysfunctionand/or overexpression of an anti-apoptotic Bcl-2 family protein,comprising administering to a subject having the disease atherapeutically effective amount of crystalline ABT-263 free base or apharmaceutical composition comprising crystalline ABT-263 free base andone or more pharmaceutically acceptable excipients. In one embodiment,the method comprises administering to the subject crystalline Form IABT-263 free base or a pharmaceutical composition comprising crystallineForm I ABT-263 free base and one or more pharmaceutically acceptableexcipients. In another embodiment, the method comprises administering tothe subject crystalline Form II ABT-263 free base or a pharmaceuticalcomposition comprising crystalline Form II ABT-263 free base and one ormore pharmaceutically acceptable excipients.

In still further embodiments of the invention, there is provided amethod for treating a disease characterized by apoptotic dysfunctionand/or overexpression of an anti-apoptotic Bcl-2 family protein,comprising (a) dissolving crystalline ABT-263 free base in apharmaceutically acceptable solvent or mixture of solvents (for exampleselected from such solvents mentioned as excipients hereinabove), and(b) administering the resulting solution in a therapeutically effectiveamount to a subject having the disease. In one embodiment, thecrystalline ABT-263 free base is crystalline Form I ABT-263 free base.In another embodiment, the crystalline ABT-263 free base is crystallineForm II ABT-263 free base.

The subject can be human or non-human (e.g., a farm, zoo, work orcompanion animal, or a laboratory animal used as a model) but in animportant embodiment the subject is a human patient in need of the drug,for example to treat a disease characterized by apoptotic dysfunctionand/or overexpression of an anti-apoptotic Bcl-2 family protein. A humansubject can be male or female and of any age. The patient is typicallyan adult, but a method of the invention can be useful to treat achildhood cancer such as leukemia, for example acute lymphocyticleukemia, in a pediatric patient.

The composition is normally administered in an amount providing atherapeutically effective daily dose of the drug. The term “daily dose”herein means the amount of drug administered per day, regardless of thefrequency of administration. For example, if the subject receives a unitdose of 150 mg twice daily, the daily dose is 300 mg. Use of the term“daily dose” will be understood not to imply that the specified dosageamount is necessarily administered once daily. However, in a particularembodiment the dosing frequency is once daily (q.d.), and the daily doseand unit dose are in this embodiment the same thing.

What constitutes a therapeutically effective dose depends on thebioavailability of the particular formulation, the subject (includingspecies and body weight of the subject), the disease (e.g., theparticular type of cancer) to be treated, the stage and/or severity ofthe disease, the individual subject's tolerance of the compound, whetherthe compound is administered in monotherapy or in combination with oneor more other drugs, e.g., other chemotherapeutics for treatment ofcancer, and other factors. Thus the daily dose can vary within widemargins, for example from about 10 to about 1,000 mg. Greater or lesserdaily doses can be appropriate in specific situations. It will beunderstood that recitation herein of a “therapeutically effective” doseherein does not necessarily require that the drug be therapeuticallyeffective if only a single such dose is administered; typicallytherapeutic efficacy depends on the composition being administeredrepeatedly according to a regimen involving appropriate frequency andduration of administration. It is strongly preferred that, while thedaily dose selected is sufficient to provide benefit in terms oftreating the cancer, it should not be sufficient to provoke an adverseside-effect to an unacceptable or intolerable degree. A suitabletherapeutically effective dose can be selected by the physician ofordinary skill without undue experimentation based on the disclosureherein and on art cited herein, taking into account factors such asthose mentioned above. The physician may, for example, start a cancerpatient on a course of therapy with a relatively low daily dose andtitrate the dose upwards over a period of days or weeks, to reduce riskof adverse side-effects.

Illustratively, suitable doses of ABT-263 are generally about 25 toabout 1000 mg/day or about 50 to about 1000 mg/day, more typically about50 to about 500 mg/day or about 200 to about 400 mg/day, for exampleabout 50, about 100, about 150, about 200, about 250, about 300, about350, about 400, about 450, about 500, about 750 or about 1000 mg/day,administered at an average dosage interval of about 3 hours to about 7days, for example about 8 hours to about 3 days, or about 12 hours toabout 2 days. In most cases a once-daily (q.d.) administration regimenis suitable.

An “average dosage interval” herein is defined as a span of time, forexample one day or one week, divided by the number of unit dosesadministered over that span of time. For example, where a drug isadministered three times a day, around 8 am, around noon and around 6pm, the average dosage interval is 8 hours (a 24-hour time span dividedby 3). If the drug is formulated as a discrete dosage form such as atablet or capsule, a plurality (e.g., 2 to about 10) of dosage formsadministered at one time is considered a unit dose for the purpose ofdefining the average dosage interval.

A daily dosage amount and dosage interval can, in some embodiments, beselected to maintain a plasma concentration of ABT-263 in a range ofabout 0.5 to about 10 μg/ml. Thus, during a course of ABT-263 therapyaccording to such embodiments, the steady-state peak plasmaconcentration (C_(max)) should in general not exceed about 10 μg/ml, andthe steady-state trough plasma concentration (C_(min)) should in generalnot fall below about 0.5 μg/ml. It will further be found desirable toselect, within the ranges provided above, a daily dosage amount andaverage dosage interval effective to provide a C_(max)/C_(mm) ratio notgreater than about 5, for example not greater than about 3, atsteady-state. It will be understood that longer dosage intervals willtend to result in greater C_(max)/C_(mm) ratios. Illustratively, atsteady-state, an ABT-263 C_(max) of about 3 to about 8 μg/ml and C_(min)of about 1 to about 5 μg/ml can be targeted by the present method.Steady-state values of C_(max) and C_(min) can be established in a humanPK study, for example conducted according to standard protocolsincluding but not limited to those acceptable to a regulatory agencysuch as the U.S. Food and Drug Administration (FDA).

As compositions useful herein are believed to exhibit only a minor foodeffect, administration according to the present embodiment can be withor without food, i.e., in a non-fasting or fasting condition. It isgenerally preferred to administer the present compositions to anon-fasting patient.

Formulations of the present invention are suitable for use inmonotherapy or in combination therapy, for example with otherchemotherapeutics or with ionizing radiation. A particular advantage ofthe present invention is that it permits once-daily oral administration,a regimen which is convenient for the patient who is undergoingtreatment with other orally administered drugs on a once-daily regimen.Oral administration is easily accomplished by the patient him/herself orby a caregiver in the patient's home; it is also a convenient route ofadministration for patients in a hospital or residential care setting.

Combination therapies illustratively include administration of acomposition comprising (or prepared using as API) crystalline ABT-263free base concomitantly with one or more of bortezomid, carboplatin,cisplatin, cyclophosphamide, dacarbazine, dexamethasone, docetaxel,doxorubicin, etoposide, fludarabine, hydroxydoxorubicin, irinotecan,paclitaxel, rapamycin, rituximab, vincristine and the like, for examplewith a polytherapy such as CHOP(cyclophosphamide+hydroxydoxorubicin+vincristine+prednisone), RCVP(rituximab+cyclophosphamide+vincristine+prednisone), R-CHOP(rituximab+CHOP) or DA-EPOCH-R (dose-adjusted etoposide, prednisone,vincristine, cyclophosphamide, doxorubicin and rituximab).

An ABT-263 composition can be administered in combination therapy withone or more therapeutic agents that include, but are not limited to,angiogenesis inhibitors, antiproliferative agents, other apoptosispromoters (for example, Bcl-xL, Bcl-w and Bfl-1 inhibitors), activatorsof a death receptor pathway, BiTE (bi-specific T-cell engager)antibodies, dual variable domain binding proteins (DVDs), inhibitors ofapoptosis proteins (IAPB), microRNAs, mitogen-activated extracellularsignal-regulated kinase inhibitors, multivalent binding proteins,poly-ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors,small inhibitory ribonucleic acids (siRNAs), kinase inhibitors, receptortyrosine kinase inhibitors, aurora kinase inhibitors, polo-like kinaseinhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), antimitoticagents, alkylating agents, antimetabolites, intercalating antibiotics,platinum-containing chemotherapeutic agents, growth factor inhibitors,ionizing radiation, cell cycle inhibitors, enzymes, topoisomeraseinhibitors, biologic response modifiers, immunologicals, antibodies,hormonal therapies, retinoids, deltoids, plant alkaloids, proteasomeinhibitors, HSP-90 inhibitors, histone deacetylase (HDAC) inhibitors,purine analogs, pyrimidine analogs, MEK inhibitors, CDK inhibitors,ErbB2 receptor inhibitors, mTOR inhibitors as well as other antitumoragents.

Angiogenesis inhibitors include, but are not limited to, EGFRinhibitors, PDGFR inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1Rinhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, matrixmetalloproteinase 9 (MMP-9) inhibitors and thrombospondin analogs.

Examples of EGFR inhibitors include, but are not limited to, gefitinib,erlotinib, cetuximab, EMD-7200, ABX-EGF, HR3, IgA antibodies, TP-38(IVAX), EGFR fusion protein, EGF-vaccine, anti-EGFR immunoliposomes andlapatinib.

Examples of PDGFR inhibitors include, but are not limited to, CP-673451and CP-868596.

Examples of VEGFR inhibitors include, but are not limited to,bevacizumab, sunitinib, sorafenib, CP-547632, axitinib, vandetanib,AEE788, AZD-2171, VEGF trap, vatalanib, pegaptanib, IM862, pazopanib,ABT-869 and angiozyme.

Bcl-2 family protein inhibitors other than ABT-263 or compounds ofFormula I herein include, but are not limited to, AT-101 ((−)gossypol),Genasense™ Bcl-2-targeting antisense oligonucleotide (G3139 oroblimersen), IPI-194, IPI-565, ABT-737, GX-070 (obatoclax) and the like.

Activators of a death receptor pathway include, but are not limited to,TRAIL, antibodies or other agents that target death receptors (e.g., DR4and DR5) such as apomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab),HGS-1029, LBY-135, PRO-1762 and trastuzumab.

Examples of thrombospondin analogs include, but are not limited to,TSP-1, ABT-510, ABT-567 and ABT-898.

Examples of aurora kinase inhibitors include, but are not limited to,VX-680, AZD-1152 and MLN-8054.

An example of a polo-like kinase inhibitor includes, but is not limitedto, BI-2536.

Examples of bcr-abl kinase inhibitors include, but are not limited to,imatinib and dasatinib.

Examples of platinum-containing agents include, but are not limited to,cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatinand satraplatin.

Examples of mTOR inhibitors include, but are not limited to, CCI-779,rapamycin, temsirolimus, everolimus, RAD001 and AP-23573.

Examples of HSP-90 inhibitors include, but are not limited to,geldanamycin, radicicol, 17-AAG, KOS-953, 17-DMAG, CNF-101,CNF-1010,17-AAG-nab, NCS-683664, efungumab, CNF-2024, PU3, PU24FC1,VER-49009, IPI-504, SNX-2112 and STA-9090.

Examples of HDAC inhibitors include, but are not limited to,suberoylanilide hydroxamic acid (SAHA), MS-275, valproic acid, TSA,LAQ-824, trapoxin and depsipeptide.

Examples of MEK inhibitors include, but are not limited to, PD-325901,ARRY-142886, ARRY-438162 and PD-98059.

Examples of CDK inhibitors include, but are not limited to,flavopyridol, MCS-5A, CVT-2584, seliciclib ZK-304709, PHA-690509,BMI-1040, GPC-286199, BMS-387032, PD-332991 and AZD-5438.

Examples of COX-2 inhibitors include, but are not limited to, celecoxib,parecoxib, deracoxib, ABT-963, etoricoxib, lumiracoxib, BMS-347070, RS57067, NS-398, valdecoxib, rofecoxib,SD-8381,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl)-1H-pyrrole,T-614, JTE-522, S-2474, SVT-2016, CT-3 and SC-58125.

Examples of NSAIDs include, but are not limited to, salsalate,diflunisal, ibuprofen, ketoprofen, nabumetone, piroxicam, naproxen,diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac andoxaprozin.

Examples of ErbB2 receptor inhibitors include, but are not limited to,CP-724714, canertinib, trastuzumab, petuzumab, TAK-165, ionafamib,GW-282974, EKB-569, PI-166, dHER2, APC-8024, anti-HER/2neu bispecificantibody B7.her2IgG3 and HER2 trifunctional bispecific antibodies mABAR-209 and mAB 2B-1.

Examples of alkylating agents include, but are not limited to, nitrogenmustard N-oxide, cyclophosphamide, ifosfamide, trofosfamide,chlorambucil, melphalan, busulfan, mitobronitol, carboquone, thiotepa,ranimustine, nimustine, Cloretazine™ (laromustine), AMD-473,altretamine, AP-5280, apaziquone, brostallicin, bendamustine,carmustine, estramustine, fotemustine, glufosfamide, KW-2170,mafosfamide, mitolactol, lomustine, treosulfan, dacarbazine andtemozolomide.

Examples of antimetabolites include, but are not limited to,methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil(5-FU) alone or in combination with leucovorin, tegafur, UFT,doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine,S-1, pemetrexed, gemcitabine, fludarabine, 5-azacitidine, capecitabine,cladribine, clofarabine, decitabine, eflornithine, ethenylcytidine,cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine,nolatrexed, disodium pemetrexed, pentostatin, pelitrexol, raltitrexed,triapine, trimetrexate, vidarabine, mycophenolic acid, ocfosfate,pentostatin, tiazofurin, ribavirin, EICAR, hydroxyurea and deferoxamine.

Examples of antibiotics include, but are not limited to, intercalatingantibiotics, aclarubicin, actinomycin D, amrubicin, annamycin,adriamycin, bleomycin, daunorubicin, doxorubicin (including liposomaldoxorubicin), elsamitrucin, epirubicin, glarubicin, idarubicin,mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin,rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin andcombinations thereof.

Examples of topoisomerase inhibiting agents include, but are not limitedto, aclarubicin, amonafide, belotecan, camptothecin,10-hydroxycamptothecin, 9-amino-camptothecin, amsacrine, dexrazoxane,diflomotecan, irinotecan HCl, edotecarin, epirubicin, etoposide,exatecan, becatecarin, gimatecan, lurtotecan, orathecin, BN-80915,mitoxantrone, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38,tafluposide and topotecan.

Examples of antibodies include, but are not limited to, rituximab,cetuximab, bevacizumab, trastuzumab, CD40-specific antibodies andIGF1R-specific antibodies, chTNT-1/B, denosumab, edrecolomab, WX G250,zanolimumab, lintuzumab and ticilimumab.

Examples of hormonal therapies include, but are not limited to,sevelamer carbonate, rilostane, luteinizing hormone releasing hormone,modrastane, exemestane, leuprolide acetate, buserelin, cetrorelix,deslorelin, histrelin, anastrozole, fosrelin, goserelin, degarelix,doxercalciferol, fadrozole, formestane, tamoxifen, arzoxifene,bicalutamide, abarelix, triptorelin, finasteride, fulvestrant,toremifene, raloxifene, trilostane, lasofoxifene, letrozole, flutamide,megesterol, mifepristone, nilutamide, dexamethasone, prednisone andother glucocorticoids.

Examples of retinoids or deltoids include, but are not limited to,seocalcitol, lexacalcitol, fenretinide, aliretinoin, tretinoin,bexarotene and LGD-1550.

Examples of plant alkaloids include, but are not limited to,vincristine, vinblastine, vindesine and vinorelbine.

Examples of proteasome inhibitors include, but are not limited to,bortezomib, MG-132, NPI-0052 and PR-171.

Examples of immunologicals include, but are not limited to, interferonsand numerous other immune-enhancing agents. Interferons includeinterferon alpha, interferon alpha-2a, interferon alpha-2b, interferonbeta, interferon gamma-1a, interferon gamma-1b, interferon gamma-n1 andcombinations thereof. Other agents include filgrastim, lentinan,sizofilan, BCG live, ubenimex, WF-10 (tetrachlorodecaoxide or TCDO),aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin,gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, melanomavaccine, molgramostim, sargaramostim, tasonermin, tecleukin, thymalasin,tositumomab, Virulizin™ immunotherapeutic of Lorus Pharmaceuticals,Z-100 (specific substance of Maruyama or SSM), Zevalin™ (90Y-ibritumomabtiuxetan), epratuzumab, mitumomab, oregovomab, pemtumomab, Provenge™(sipuleucel-T), teceleukin, Therocys™ (Bacillus Calmette-Guerin),cytotoxic lymphocyte antigen 4 (CTLA4) antibodies and agents capable ofblocking CTLA4 such as MDX-010.

Examples of biological response modifiers are agents that modify defensemechanisms of living organisms or biological responses, such assurvival, growth, or differentiation of tissue cells to direct them tohave anti-tumor activity. Such agents include, but are not limited to,krestin, lentinan, sizofuran, picibanil, PF-3512676 and ubenimex.

Examples of pyrimidine analogs include, but are not limited to,5-fluorouracil, floxuridine, doxifluridine, raltitrexed, cytarabine,cytosine arabinoside, fludarabine, triacetyluridine, troxacitabine andgemcitabine.

Examples of purine analogs include, but are not limited to,mercaptopurine and thioguanine

Examples of antimitotic agents include, but are not limited to,N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,paclitaxel, docetaxel, larotaxel, epothilone D, PNU-100940, batabulin,ixabepilone, patupilone, XRP-9881, vinflunine and ZK-EPO (syntheticepothilone).

Examples of radiotherapy include, but are not limited to, external beamradiotherapy (XBRT), teletherapy, brachytherapy, sealed-sourceradiotherapy and unsealed-source radiotherapy.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies include, butare not limited to, adecatumumab (Micromet MT201), blinatumomab(Micromet MT103) and the like. Without being limited by theory, one ofthe mechanisms by which T-cells elicit apoptosis of the target cancercell is by exocytosis of cytolytic granule components, which includeperforin and granzyme B. In this regard, Bcl-2 has been shown toattenuate the induction of apoptosis by both perforin and granzyme B.These data suggest that inhibition of Bcl-2 could enhance the cytotoxiceffects elicited by T-cells when targeted to cancer cells (Sutton et al.(1997) J. Immunol. 158:5783-5790).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand. For example, siRNAs targeting Mcl-1 have beenshown to enhance the activity of ABT-263 (Tse et al. (2008), supra, andreferences therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising twoheavy-chain DVD polypeptides and two light-chain DVD polypeptides arereferred to as DVD Ig's. Each half of a DVD Ig comprises a heavy-chainDVD polypeptide, a light-chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy-chain variable domain and alight-chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site.

PARP inhibitors include, but are not limited to, ABT-888, olaparib,KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 andthe like.

Additionally or alternatively, a composition comprising (or preparedusing as API) crystalline ABT-263 free base can be administered incombination therapy with one or more antitumor agents selected fromABT-100, N-cetylcolchinol-O-phosphate, acitretin, AE-941, aglyconprotopanaxadiol, arglabin, arsenic trioxide, AS04 adjuvant-adsorbed HPVvaccine, L-asparaginase, atamestane, atrasentan, AVE-8062, bosentan,canfosfamide, Canvaxin™, catumaxomab, CeaVac™, celmoleukin, combrestatinA4P, contusugene ladenovec, Cotara™, cyproterone, deoxycoformycin,dexrazoxane, N,N-diethyl-2-(4-(phenylmethyl)phenoxy)ethanamine,5,6-dimethylxanthenone-4-acetic acid, docosahexaenoic acid/paclitaxel,discodermolide, efaproxiral, enzastaurin, epothilone B, ethynyluracil,exisulind, falimarev, Gastrimmune™, GMK vaccine, GVAX™, halofuginone,histamine, hydroxycarbamide, ibandronic acid, ibritumomab tiuxetan,IL-13-PE38, inalimarev, interleukin 4, KSB-311, lanreotide,lenalidomide, lonafarnib, lovastatin, 5,10-methylenetetrahydrofolate,mifamurtide, miltefosine, motexafin, oblimersen, OncoVAX™, Osidem™,paclitaxel albumin-stabilized nanoparticle, paclitaxel poliglumex,pamidronate, panitumumab, peginterferon alfa, pegaspargase, phenoxodiol,poly(I)-poly(C12U), procarbazine, ranpirnase, rebimastat, recombinantquadrivalent HPV vaccine, squalamine, staurosporine, STn-KLH vaccine, T4endonuclase V, tazarotene,6,6′,7,12-tetramethoxy-2,2′-dimethyl-1β-berbaman, thalidomide,TNFerade™, ¹³¹I-tositumomab, trabectedin, triazone, tumor necrosisfactor, Ukrain™, vaccinia-MUC-1 vaccine, L-valine-L-boroproline,Vitaxin™, vitespen, zoledronic acid and zorubicin.

In one embodiment, a composition comprising (or prepared using as API)crystalline ABT-263 free base is administered in a therapeuticallyeffective amount to a subject in need thereof to treat a disease duringwhich is overexpressed one or more of antiapoptotic Bcl-2 protein,antiapoptotic Bcl-X_(L) protein and antiapoptotic Bcl-w protein.

In another embodiment, a composition comprising (or prepared using asAPI) crystalline ABT-263 free base is administered in a therapeuticallyeffective amount to a subject in need thereof to treat a disease ofabnormal cell growth and/or dysregulated apoptosis.

Examples of such diseases include, but are not limited to, cancer,mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, ovarian cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, bone cancer, colon cancer, rectalcancer, cancer of the anal region, stomach cancer, gastrointestinal(gastric, colorectal and/or duodenal) cancer, chronic lymphocyticleukemia, acute lymphocytic leukemia, esophageal cancer, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,testicular cancer, hepatocellular (hepatic and/or biliary duct) cancer,primary or secondary central nervous system tumor, primary or secondarybrain tumor, Hodgkin's disease, chronic or acute leukemia, chronicmyeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia,follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin,melanoma, multiple myeloma, oral cancer, non-small-cell lung cancer,prostate cancer, small-cell lung cancer, cancer of the kidney and/orureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasmsof the central nervous system, primary central nervous system lymphoma,non Hodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, adrenocortical cancer, gall bladder cancer, cancer of thespleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastomaor a combination thereof.

In a more particular embodiment, a composition comprising (or preparedusing as API) crystalline ABT-263 free base is administered in atherapeutically effective amount to a subject in need thereof to treatbladder cancer, brain cancer, breast cancer, bone marrow cancer,cervical cancer, chronic lymphocytic leukemia, acute lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small-cell lung cancer, prostate cancer,small-cell lung cancer or spleen cancer.

According to any of these embodiments, the composition can beadministered in monotherapy or in combination therapy with one or moreadditional therapeutic agents.

For example, a method for treating mesothelioma, bladder cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, ovarian cancer, breast cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, bone cancer, colon cancer, rectal cancer, cancer of the analregion, stomach cancer, gastrointestinal (gastric, colorectal and/orduodenal) cancer, chronic lymphocytic leukemia, acute lymphocyticleukemia, esophageal cancer, cancer of the small intestine, cancer ofthe endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, testicular cancer,hepatocellular (hepatic and/or biliary duct) cancer, primary orsecondary central nervous system tumor, primary or secondary braintumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloidleukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,multiple myeloma, oral cancer, non-small-cell lung cancer, prostatecancer, small-cell lung cancer, cancer of the kidney and/or ureter,renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of thecentral nervous system, primary central nervous system lymphoma, nonHodgkin's lymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, adrenocortical cancer, gall bladder cancer, cancer of thespleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastomaor a combination thereof in a subject comprises administering to thesubject therapeutically effective amounts of (a) a compositioncomprising (or prepared using as API) crystalline ABT-263 free base and(b) one or more of etoposide, vincristine, CHOP, rituximab, rapamycin,R-CHOP, RCVP, DA-EPOCH-R or bortezomib.

In particular embodiments, a composition comprising (or prepared usingas API) crystalline ABT-263 free base is administered in atherapeutically effective amount to a subject in need thereof incombination therapy with etoposide, vincristine, CHOP, rituximab,rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib in a therapeuticallyeffective amount, for treatment of a lymphoid malignancy such as B-celllymphoma or non-Hodgkin's lymphoma.

In other particular embodiments, a composition comprising (or preparedusing as API) crystalline ABT-263 free base is administered in atherapeutically effective amount to a subject in need thereof inmonotherapy or in combination therapy with etoposide, vincristine, CHOP,rituximab, rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib in atherapeutically effective amount, for treatment of chronic lymphocyticleukemia or acute lymphocytic leukemia.

Further information of relevance to the present invention is availablein a recently published article by Tse et al. (2008) Cancer Res.68:3421-3428 and supplementary data thereto available at Cancer ResearchOnline (cancerres.aacrjournals.org/). This article and its supplementarydata are incorporated in their entirety herein by reference.

What is claimed is:
 1. The compoundN-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamidefree base in a solid crystalline Form II, characterized at least by apowder X-ray diffraction peak at any one or more of the followingpositions: 5.79, 8.60, 12.76, 15.00 and 20.56°2θ, ±0.2°2θ.
 2. A processfor preparing a pharmaceutical solution composition of ABT-263,comprising dissolving the compound of claim 1 in a pharmaceuticallyacceptable solvent or mixture of solvents.